Short stature and metabolic abnormalities in two sisters with a 7.6-kb GH1 gene deletion☆
Introduction
Growth hormone 1 (GH1) gene deletions occur in ~ 10–15% of patients with severe isolated GH deficiency (GHD) and marked short stature [height standard deviation (SD) score < −4.5] [1], [2]. The GH1 gene is part of a GH gene cluster consisting of four other structural genes: chorionic somatomammotropin-like (CSL), chorionic somatomammotropin (CS1), GH2, and CS2 [3]. The genes for CSL, CS1, CS2, and GH2 are expressed by placental villi, while that for GH1 is mainly expressed in somatotroph cells of the anterior pituitary. The GH1 gene, mapped to chromosome 17q23–q24 [4], encodes for human GH, a protein with a molecular mass of 22,005 Da that contains 191 amino-acid residues with two disulfide bridges [5]. Flanking the GH1 gene are multiple highly homologous regions that allow susceptibility to recombination mutations and subsequent gene deletions.
Through a series of receptor-mediated signal transduction pathways, GH induces the production of IGF-I, which, in turn, regulates linear growth. Besides skeletal growth, GH also influences bone mineral density [6] and body composition [7]. Classically, disruptions in the GH-IGF-I axis are phenotypically associated with short stature with proportional limb lengths relative to the trunk, cranio-facial disproportion including frontal bossing, truncal obesity, and mild delay in puberty.
Since 1985, patients with GH deficiency have been treated with recombinant human GH (rhGH). A caveat to this treatment paradigm may occur in individuals with certain types of GH1 gene deletions. Depending on the nature of the genetic mutation causing the GH1 gene deletion, as well as the inability of the immune system to recognize endogenous GH, neutralizing antibodies may develop in response to exogenous rhGH administration which negate any beneficial effect from its use [8].
With the FDA approval of recombinant human IGF-I (rhIGF-I) in 2005, an alternative to rhGH for promoting statural growth in children with GH1 gene deletions and neutralizing GH antibodies became available. Herein, we describe the growth patterns and metabolic status of two Hispanic sisters with 7.6-kb GH1 gene deletions, the older of whom reached close to her genetic target height range despite only short-term treatment with rhGH and the younger of whom has been treated for 4 yr with rhIGF-I.
Section snippets
Methods
Blood samples were collected under informed consent. DNA was extracted from EBV-transformed lymphocytes. For Southern blot analysis, DNA was digested to completion with BamH I, separated on 1% agarose gels, and transferred to nylon membranes. The blots were hybridized with a CS1 cDNA probe labeled with 32P [9]. Autoradiographs of the blots were analyzed densitometrically using a Bio-Rad ChemDocXR image analyzer. Image Lab software Bio-Rad (Hercules, CA) was used to compare relative gene dosage
Discussion
Phillips and Cogan have described at least four Mendelian forms of familial isolated IGHD [12]. IGHD Type 1A is due to autosomal recessive inheritance that leads to the deletion of the GH gene and subsequent undetectable serum levels of GH protein. IGHD Type IB is also inherited in an autosomal recessive fashion, but is associated with a splice-site mutation associated with detectable serum levels of GH. IGHD Type 2 is an autosomal dominant mutation and can be associated with a variety of
Acknowledgements
We thank Laura Sexton and Tamara Murphy for technical assistance with the DNA analysis.
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Dr. Ahmad wrote the first draft of this manuscript and did not receive any payment, honorarium, or grant to produce this manuscript.